Etching was first used as a printmaking technique in the mid-1490s by the Augsburg printmaker and armor decorator Daniel Hopfer. Augsburg had long been known for its armorers and the etched decoration of steel and iron. Collaboration among the city's close network of craftsmen and artists ultimately led to the reimagining of the etching technique, as etched designs and compositions began to be produced on paper and shared with a wider market. Hopfer was extremely innovative in his use of the medium, deploying a combination of techniques to achieve a range of textures and effects, all displayed in his tour de force Death and the Devil Surprising Two Women.

Some of the most prolific and accomplished printmakers in Germany experimented with etching in the early sixteenth century. Albrecht Dürer made six etchings. The Large Cannon, his final and most adept experiment in the medium, showed not only how the etched line could approximate the drawn one, but also how etching could be used to depict landscape to extraordinary effect.

In the Netherlands, a small group of artists began to etch in the early 1520s. Certain practitioners, such as Jan Gossart, Lucas van Leyden, and Dirk Vellert, briefly flirted with the technique, producing just a few prints. Others, namely Frans Crabbe and Nicolaas Hogenberg, engaged in a more serious relationship. Lucas was, crucially, the first artist in Europe to etch on copper, a softer metal that allowed greater flexibility in handling; it rapidly became the metal of choice for this technique. Copper plates permitted the mixing of etching with engraving and were not vulnerable to the metal corrosion that plagued the German etchers who worked on iron.

The early etchers of the Netherlands lived across the country, in the court cities of Mechelen and Wijk by Duurstede and the market-driven cities of Antwerp and Leiden. As a group, their etchings are less freely sketched than those of artists in other parts of Europe. They brought to the medium the tight hatching systems characteristic of engraving. Humanist scholars and patrons, situated at the courts, were fascinated by new technologies and the innovations of these artists. They became instrumental in the promotion and circulation of etching throughout the region.

About 1520, the practice of etching in Germany entered a second phase. By that point, Albrecht Dürer had abandoned the technique, and Netherlandish artists were taking it up, Lucas van Leyden most prominent among them. While their counterparts in the Netherlands had begun to use copper plates, German etchers such as Albrecht Altdorfer largely stuck with iron. Nevertheless, they expanded the notion of what the medium could achieve. Building on the accomplishments of Dürer, Altdorfer produced the first independent printed landscapes, which prominently displayed his distinctive calligraphic freedom.

Augustin Hirschvogel and Hanns Lautensack, first in Nuremberg and then in the Habsburg capital Vienna, also turned their attention to landscape. They produced topographic views of known places, mathematically precise maps, and invented vistas, among other subjects. In the 1540s, Hirschvogel worked exclusively with copper plates, which suited his personal style with its decorative flourishes and looping lines. Lautensack experimented with iron, but shifted to copper in the 1550s during the height of his activity as an etcher, and often mixed etched lines with engraving. Lautensack's print operation also became more organized and prolific: he began publishing his etchings in series and may have engaged professional printers. From the 1520s on, German artists embraced etching as a primary printmaking technique and began to test different ways to expand the market for their prints.

A leading proponent of the Mannerist style and one of the most talented draftsmen of his generation, Francesco Parmigianino was the first Italian artist to fully exploit the possibilities of etching. During his short stay in Bologna between 1527 and 1530, he became deeply involved in printmaking, executing etchings and creating designs for chiaroscuro woodcuts. The appetite for his drawings among a new, sophisticated class of collector provided the main stimulus for his short career as a printmaker. Numbering only eighteen, his delicate, mostly small-scale etchings were immensely influential and widely admired by artists and collectors for their technical skill and exquisite figural compositions. The ingenuity and elegant draftsmanship of his etchings continued to be appreciated in subsequent centuries, earning him the title of the first true "painter-etcher." Furthermore, his experiments with colored inks, plate tone, and pairing of etching with woodcut mark him as one of the great pioneers of the print medium.

In the years immediately following Parmigianino's departure from Bologna, a handful of artists, including Bartolomeo Passarotti and Giulio Bonasone, continued to practice etching in the city, but it was further north in the Veneto that the medium saw its greatest flourishing in Italy.

From about 1530 to 1560, following Parmigianino's printmaking activities in Bologna, etching was mainly a northern Italian phenomenon. The medium flourished in the wealthy cities of Venice and Verona, deployed primarily by painters who, like Parmigianino, were skillful draftsmen. Artists such as Battista del Moro, Angelo Falconetto, and Battista Franco delighted in the technique's proximity to drawing and its rich aesthetic possibilities. They produced a variety of prints, from carefully executed figural compositions after some of the leading artists of the day to landscapes drawn in a free and fluid manner. Indeed, etching was particularly well suited to the depiction of landscape, a subject that developed as an autonomous genre during the period and was widely appreciated among a new generation of connoisseur collector.

By the early 1560s, etching had evolved from a sporadic production, representing only a tiny proportion of the prints produced in Italy, into a favored medium of professionals working in the extremely successful print, book, and map industries in Venice and Rome.

Etching arrived on the scene in France about 1540, considerably later than in Germany and the Low Countries, and more than a decade after Parmigianino's forays into the medium in Italy. The technique was adopted at the height of the French Renaissance, a period of great cultural significance in France, when artists working for King Francis I established a new visual and ornamental language. A widespread interest in antiquarianism also fueled the demand for printed images among the French elite. Artists and craftsmen of all backgrounds took up etching, from sculptors and architects to enamel painters and illuminators. Free from the usual constraints of traditional patronage, the medium enabled them to produce some of the most whimsical and expressive images of the French Renaissance.

Two particularly ambitious printmaking enterprises emerged in the 1540s. In Paris, the architect and draftsman Jacques Androuet du Cerceau began producing numerous etchings devoted to ornamental and architectural subjects, while at the nearby château of Fontainebleau, a group of artists turned their attention to the medium in a flurry of activity that lasted about five years. Their prints would have a profound effect on the course of French art, widely disseminating the new courtly style that originated in the rooms and galleries of Fontainebleau.

By the mid-1550s, etchings were becoming an important component of the stocks of enterprising publishers within the growing market for prints in the Netherlands. The technique had migrated from artists' studios and small circles of courtly enthusiasts to the broad art market, with its international reach. For financially minded publishers like Hieronymus Cock and Bartholomeus de Momper, etching offered an expedient alternative to engraving. Once the technique had been mastered, printmakers could produce large series of prints quickly and effectively, saving time and money. The wealthy port city of Antwerp, with its intellectual, art-loving public and its access to shipping, became a magnet for ambitious publishers, talented painters, and skilled printmakers. From Antwerp, publishers could relatively quickly circulate prints throughout Europe.

During this period, two general categories of etchers emerged: professional etchers, like Peeter van der Borcht and the brothers Jan and Lucas van Doetecum, who produced prints after the designs of other artists that displayed the precision of engraving; and painter-etchers, like Pieter Bruegel and Frans Floris, who executed their own remarkable, freely-sketched etchings.